Penicillin salt



Patented Sept. 11, 1951 PENICILLIN SALT Harley W. Rhodehamel, Jr., Indianapolis, Ind., assignor to Eli Lilly and Company, Indianapolis, Ind., a corporation of Indiana No Drawing. Application June 1, 1948, Serial No. 30,501

7 Claims.

My invention relates to penicillin and more particularly to a novel and useful salt of penicillin.

An object of my invention is to provide an insoluble salt of penicillin. Another object is to provide a process whereby the isolation of substantially pure penicillin from a solution of crude penicillin may be accomplished readily. Another object is to provide an insoluble salt of penicillin capable of prolonging th therapeutic effectiveness of penicillin. Other objects will be apparfint from the following description of my invenion.

In the accomplishment of the above and other :objects, I have provided a novel penicillin salt which displays a low solubility in water and the common organic solvents, thereby affordin a convenient means of isolating penicillin from solutions thereof. Moreover, my novel penicillin salt when administered in suitable therapeutic form as described hereinafter, will provide a therapeutically effective blood concentration of penicillin for a period of 24 hours or more.

My novel penicillin salt comprises the 9-aminoacridine salt of penicillin and may be represented by the following formula NHLHP wherein I-IP represents the acidic form of penicillin.

The above-depicted novel chemical composition' may be prepared by chemical reactions of addition ormetathesis. Thus, for example, the acidic form of penicillin may be reacted with the basic 9-aminoacridine, or a metallic or metalliclike salt of penicillin may be reacted with an acid addition salt of 9-aminoacridine, the reactions preferably being carried out in a solvent in which all of the chemical components except the 9-aminoacridine salt of penicillin are soluble.

As used hereinabove the term "penicillin is used in its generic sense as in clusive of the several penicillins produced by the customary moldgrowth processes of penicillin production. Thus by the term penicillin I include the several particular penicillins known to be produced by the usual mold-growth methods. Illustrative of the mold-growth products are penicillin G (benzylpenicillin), penicillin F, penicillin dihydro F, penicillin K, penicillin X and the like.

For the sake of convenience, the following examples and illustrations which set forth the several aspects of. my invention generally will be drawn'with respect to benzyl penicillin, but it is to be understood that my invention is not limited to this particular penicillin but may be em- Example 1 g. of pure sodium benzyl penicillin are dissolved in 7 liters of cold (5 C.) water. Sufiicient sulfuric acid is added to reduce the pH of the solution to about 2.2, and the aqueous solution is extracted with about 7 liters of amyl acetate. To the amyl acetate extract which contains benzyl penicillin in its acidic form are added slowly and with vigorous stirring 4 liters of a cold solution of amyl acetate having dissolved therein about 35 g. of 9-aminoacridine. Upon addition of the 9-aminoacridine solution, yellow crystals of the Q-aminoacridine salt of benzyl penicillin separate. The crystals are separated by filtration, washed with acetone and dried in an evacuated chamber. 1

Example 2 A solution of penicillin (substantially benzyl penicillin but containing some penicillins F, dihydro F, and K) in amyl acetate is obtained ac: cording to known commercial methods by grow? ing a penicillin-producing mold and extracting the mold-growth culture medium with amyl acetate andclarifying the extract. To 14 liters of this amyl acetate solution containing about 10 g. of penicillin in acidic form are added slowly and with stirring, 450 ml. of amyl acetate wherein 5 g. of aminoacridine are substantially completely dissolved. The initial precipitate of the 9-aminoacridine salt of the penicillin is of amorphous 1 The penicillin is recovered from its insoluble.

Q-aminoacridine salt as follows: 0.5 g. of the Q-aminoacridine salt of penicillin are dissolved in about 500 m1. of cold water and sufficient sulfuric acid is slowlyadded to acidify the solution to about pH -2.

upon the penicillin dissolves in the amyl acetate and the 9-aminoacridine in the form of its sulfate salt dissolves in the aqueous phase. amyl acetate layer is separated from the aqueous layer, and the penicillin is recovered in purified form from the amyl acetate by extraction of the amyl acetate with dilute aqueous alkali, or by any of the other known isolated procedures.- By

isolation procedures of the above and similar The acidified mixture is ex tracted with about ml. of amyl acetate, where- The being as much as 25 percent or more when relatively crude penicillin preparations are employed.

Example 3 To a solution of 5 g. of the potassium salt of substantially pure benzyl penicillin in 100 ml. of cold water, is added slowly andwith stirring a a therapeuticallyeffective blood concentration of penicillin for at least2-4 hours;

An additional illustrative example of a medicinal composition comprises a suspension in 127 ml. of sesame oil of 50 g. of the Q-aminoacridine salt of benzyl penicillin ground to ZOO-mesh screen 1 size. .A medicinal preparation having these prosolution of 3.2 g. of 9-aminoacridine hydrochlo- I ride suspended and dissolved in 100 ml. of water.

The 9-aminoacridine salt precipitates in crystalline form. The salt is separated by filtration;

and dried.

Example 4 To 500 ml. of an aqueous solution containing a mixtureof the impuresodium salts oflpenicil- 1ins-- G, F, dihydro E, and in the amount. of about g., are added about 15 g. of Q-aminoacridine sulfate, dissolved andsuspended in 200 ml. of water. The precipitate of the Q-aminoacridine salt-0f penicillin which separates is filtered off and dried.

The 9-aminoacridine salt of penicillin which acridine salts of penicillin F, dihydro F, etc.,-

have melting points approximatin the above value.

For therapeutic purposes the Q-aminoacridine salt of. penicillin is administered intramuscularly as a..finely.divided suspension of the saltin a liquid vehic1e. Suitable. vehicles for the provision of.injectab1e suspensions include aqueous and-oleaginous .vehicles, for example. water, and vegetableoils such as cottonseed, sesameoil and the like. .As will be readilyunderstood, the particlesize of the salt shouldhbe sufiiciently small; to permit the particles to .pass. readily :through, the lumenof a hypodermic needle. without packing withinand blocking the needle; Illustrative.-

ly, a particle size which avoids blocking of a 20- gauge needle -is that which. will readily-pass.

througha 200-mesh screenaw By wayofillustration, an aqueous medicinal composition which upon intramuscular injection is capable'of maintaining a'therapeutically effective blood level of penicillin for a-period of at least- 24 hours comprises a suspension containing about:300 mg. of the finely divided Q-aminoacridine salt of benzyl penicillin per ml. of water.

Since, asis known, penicillin is relatively unstable inthe presence of appreciable amounts of moisture, aqueous compositions containing-the Q-aminoacridinesalt of penicillin should be used within a comparatively short time after their preparation, For this reasonit is often dGSll".

able to provide medicinal compositions comprising suspensions of the Q-aminoacridinesalt of penicillin in oleaginous vehicles, A suitable oleaginous composition is, prepared ,by suspending in,15.5 ml. of cottonseed oil 6 g. of the 9- aminoacridine salt of penicillin ground to such particle size thatall of. the material will pass through a, ZOO-mesh screen. Intramuscular injection Qfql m1. of this suspension will maintain portionscontains about 300,000 Oxford units of penicillin per ml, and when administered intramuscularly in an amount of 1 ml. is capable of maintaining for at least 24 hours an effective blood concentration of penicillin greater than about 0.03 Oxford units per ml. of blood, this concentration being considered the minimal efiective concentration.

It is to be understood that the above-mentioned medicinal preparations are given by wayof illustrationonly and -it.will'be apparent tov those skilled in the art that there may be preparednumerous modificationsand.variations of the medicinal compositions as set forth herein.

I claim:

1. A compoundrepresented by the following formula NHLH P wherein HP represents .the acidic form of penicillinq 2. The"9 -aminoacridine salt of benzyl penicillin.

3. A therapeutic composition comprising a.

liquid, injectablesuspending medium and solid 9-aminoacridine .salt of penicillin .in finelydivided particle size, said penicillin salt being present in an amount greater than will dissolve to saturate the suspending medium."

4. A composition according to claim 3 in which the suspending mediumds'an aqueous suspending medium.

5. A composition according to claim 4 in which the penicillin salt is asalt of penicillin G.

6. A composition, according to claim 3 in which the suspending'medium is an oleaginous suspending..medium..

'7. A composition. according to. c1aim'16 in which the penicillin salt isqa salt of penicillin i HARLEYQW. RHODEHAMEL; JR.

REFERENCES CITED" The followingreferences are of arecord'in'the file ofthis patentr-v UNITED STATES' PATENTS Number Name Date 2,504,182; Cooper;- Apr. 18, 1950 OTHERREFERENCES.

Monashr. Sciencej vol. 107,0ctober .17; 1947; 1

page 370.11:

Ge0rge:.:et;al-.: {:Naturefiwol. 158, November Meleneyz, ProgressBeport No, 23.,- Committee 1 I on Medical Research; OSRD Contract .OEMcmr 80, May 15, 1945.

Heyden Report .CMR.-H;,-4,. J une 15,. 19.44.,} British Report -CL/.[R:-BI'-1-234CPs687,, freceived in-U. S. April 18,, 194.6... 1 I

Merck Report CMR-M-W, September 28, 1945.... I 

3. A THERAPEUTIC COMPOSITION COMPRISING A LIQUID, INJECTABLE SUSPENDING MEDIUM AND SOLID 9-AMINOACRIDINE SALT OF PENCILLIN IN FINELYDIVIDED PARTICLE SIZE, SAID PENCILLIN SALT BEING PRESENT IN AN AMOUNT GREATER THAN WILL DISSOLVE TO SATURATE THE SUSPENDING MEDIUM. 